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New Antidepressant GLYX-13 (Clinical Trials): Partial NMDA Receptor Agonist

A new antidepressant chemically named “GLYX-13” was developed by the biotech company Naurex for individuals with treatment-resistant depression. It is currently in clinical trials as an antidepressant augmentation strategy, meaning it is used as an add-on to already approved treatments. However, most evidence would suggest that it works extremely well as a standalone treatment option.

With the overwhelming number of individuals unable to find relief for depression, development of new antidepressants with unique properties is critical. It is estimated that over 40% of individuals who take an antidepressant medication either get no relief or actually end up feeling worse. This new drug GLYX-13 may be highly useful in treating depression due to the fact that it can work in just 2 hours, is twice as effective as current antidepressants, and following administration, antidepressant effects can last a full week.

What is GLYX-13?

GLYX-13 is considered a novel NMDA receptor modulator. It was developed by the company Naurex and is thought to act specifically on the glycine site of the NMDA receptor. Some sources characterize the drug as a “weak” selective NMDA receptor partial agonist.

It is capable of crossing the blood-brain barrier with high efficiency and at a rapid rate due to the fact that it is a “tetrapeptide.” Unlike traditional antidepressant medications that are available orally in “pill” format, GLYX-13 is not. This drug must be administered via injection, but oral formulations are in development.

Note: It should be noted that there is a similar drug also in development with the same company called “NRX-1074” that also acts as an NMDA receptor modulator.  In other words, it acts similarly, but is thought to be more potent and is also available as an oral formulation.

GLYX-13: Partial NMDA Receptor Agonist

There are several factors that differentiate GLYX-13 from other antidepressants on the market. These include: administration method, mechanism of action, length of antidepressant response, side effects, and the effect size.

  • Administration: Currently it is only available for administration via intravenous injection. There is no oral formulation (e.g. pill) of this substance. The developers are currently working to develop a pill form of the drug, but as of now all research is being conducted with the injections.
  • Antidepressant response: Current evidence from the studies suggest that the antidepressant effects from GLYX-13 are capable of lasting a full week (7 days) after an injection. Upon repeated dosages (during the stabilization period), the efficacy of the drug continues to increase over the next 6-weeks. What’s interesting is that even after a withdrawal period, reports indicated that participants never reached their initial “baseline” scores pre-treatment. This suggests that taking the drug and then withdrawing may leave you at a happier baseline than pre-treatment; whether this is true is debatable.
  • Effect size: The effect size was nearly double that of other common antidepressant drugs after 4 to 6 weeks of treatment. In other words, individuals given this medication could be considered twice as “improved” as those who find relief from traditional antidepressants.
  • Glutamate-targeting: GLYX-13 functions by altering glutamate pathways which increase neuronal communication and cellular plasticity. When our brain cells don’t communicate well with each other and/or we have poor cellular plasticity, this can lead to a variety of central nervous system disorders. It seems as though directly targeting these aspects of brain functioning can produce an antidepressant response.  It is believed to elicit its antidepressant effect specifically in the prefrontal cortex of the brain through plasticity of synapses (as induced by the NDMA receptor).
  • More “universally effective”: Although this antidepressant is not effective in everyone, it is considered more universally effective than current SSRIs, SNRIs, etc. Many people find that taking current generation antidepressants just don’t cut it for their depression. Some individuals actually end up feeling worse because they didn’t need to inhibit reuptake of serotonin. This drug seems to be working for nearly everyone – including “treatment resistant” cases of depression.
  • Neuroprotective / Nootropic potential: In rodent studies, this drug provided neuroprotection by slowing the death of various neurons in oxygen-deprived brains. In other rodent studies, it was shown that this substance improved various aspects of cognition including learning and memory functions. It is believed to enhance genetic expression in the hippocampus among rodents. It is unknown if there are similar effects to be had in humans.
  • Less side effects: It is thought that this medication has less side effects than current drugs on the market. Although it is unlikely devoid of side effects, there were no significant adverse effects reported thus far in the research. As more data is collected, we will know more about GLYX-13’s side effect profile. No participants discontinued from the research with this drug due to adverse effects.
  • Rapid onset of action: Depressive symptoms were noted as being treated within 2 hours of receiving a GLYX-13 injection. This occurred among individuals who hadn’t experienced any antidepressant relief when using other drugs. This response lasted for a full 7 days following administration.  The rapid onset of action may be similar to how ketamine treats anhedonia prior to depression.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24251380

Thoughts from Developers and Investigators

An investigator of the University of Kansas was quoted as saying, “Currently marketed antidepressants all work via similar pathways in the brain and do not adequately treat 45 percent of individuals with major depression. This presents a huge problem.” He went on to discuss the fact that many investigational antidepressants are showing significant promise to those with refractory forms of depression.

The CEO of the company Naurex (developer of the drug) stated, “The inadequacies of existing therapies have increased interest in the antidepressant properties of NMDA receptor antagonists like ketamine, but the serious side effects of these drugs limit their practical utility. After evaluating GLYX-13 in over 500 subjects to date, we believe our novel mechanism has achieved the right balance in selectively modulating the NMDA receptor to achieve the speed and efficacy of the NMDA receptor antagonists, but without the side effects.

GLYX-13 vs. Lanicemine

You may recall awhile back the development of the drug Lanicemine (AZD6765) which was being developed by AstraZeneca. They had attempted to isolate the antidepressant effects of ketamine and provide it in pill form. Unfortunately this pill never made it through FDA trials for a number of largely unknown reasons.

It is thought that Lanicemine was fairly problematic and had a number of unwanted side effects. However GLYX-13 is a similar class of medication to Lanicemine – acting on the NMDA receptor, but appears to work extremely well with minimal side effects. Some would argue that it’s the long-lost drug that AstraZeneca was originally trying to create.

GLYX-13 Clinical Trials: Expected Availability

As of March 3, 2014 – the FDA had allowed the drug to be granted “Fast Track” status for an adjunct treatment in treatment-resistant, major depressive disorder. In December 2014, the drug had finished Phase II (B) of clinical trials within the realm of “Fast Track” testing. It is expected that Phase III clinical trials will commence sometime in 2015.

The Phase II (B) data from the GLYX-13 trials was presented in December 2014 at an annual meeting of the American College of Neuropsychopharmacology. The results suggested that individuals that had been administered GLYX-13 reported “robust and sustained antidepressant effects.” These were individuals that had previously gotten no relief from other antidepressant medications.

Additionally, GLYX-13 was considered well-tolerated with no reported adverse effects or serious side effects. Unlike other NMDA receptor antagonists (e.g. Ketamine), users of GLYX-13 didn’t experience any dissociative or psychosis-esque reactions. Perhaps what’s most intriguing about GLYX-13 is the fact that it elicits a rapid-antidepressant effect (within a couple hours).

GLYX-13: Phase II(B) Study Design

The study for this drug was divided into three sections: a 6-week dose treatment stabilization period, followed by a 6-week randomized withdrawal period, and a 4-week “wash-out” phase. The study was designed to better understand the efficacy and safety of the drug with repetitive dosing as well as to determine the optimal dosage (5 mg/kg or 10 mg/kg) and dosing intervals (weekly vs. bi-weekly) to adequately treat and manage depression.

All participants in the study were rated by independent (unaffiliated) raters using the HDRS-17 scale. The participants and the raters were uninformed about the study design. A total of 386 participants were administered GLYX-13 via intravenous injection during the stabilization period until a response was established. When a response was achieved, these participants were given weekly injections of a placebo to promote a depression relapse.

When the participants relapsed, they were given GLYX-13 again to determine whether an antidepressant response could be reestablished. The study was continued with administration of GLYX-13 or a placebo for a full 6 weeks. During the second phase or the “withdrawal period” the participants were randomized and either received GLYX-13 or a placebo. During the “wash-out” phase, all of the subjects were injected with a placebo.

Results from Phase II (B): Elicit and reestablish antidepressant response

The study indicated that the GLYX-13 was significantly more effective than a placebo in treating symptoms of depression. It was also found that the drug was capable of providing antidepressant effects after a forced withdrawal period. Many current antidepressant medications won’t work as well if you try taking them after a withdrawal period; this drug seems to be different.

Those who responded to the drug showed an average decrease of 2.8 points on their HDRS-17 scores within just one week of receiving GLYX-13. When the drug was discontinued and a placebo was administered, HSRS-17 scores increased within the following week by an average of 3.1 points. After a participant stabilized on the GLYX-13, their depression scores dropped by 4.9 points on the HDRS-17 compared to their baseline (pre-treatment) scores.

The average cumulative effect of the drug lead to a decrease of 12.5 points on the HDRS-17 from their baseline after 6-weeks of treatment.

Phase III Trials: Slated for 2015

Naurex has met with the FDA and is continuing their trials with Phase III which is slated to begin in 2015. The company completed an $80 million development plan and is working on an oral version of the drug. This development plan will also work to create NMDA receptor modulators to treat other disorders of the CNS (central nervous system).

A doctor affiliated with the study stated, “We have discussed the wealth of GLYX-13 data with the FDA and have a clear understanding of the Phase 3 trial design needed to file a New Drug Application and ultimately offer this potentially important new therapy to the millions of patients who are poorly served by current treatments.”

Final thoughts on GLYX-13 for depression

Most drug companies are currently working on variations of current drugs on the market. GLYX-13 shows significant promise for usage in psychiatry and could potentially help a large percentage of individuals who don’t get relief from standard antidepressant treatment options. Additionally unlike the futuristic “Triple Reuptake Inhibitors,” it isn’t a variation of any current antidepressants on the market, making it unique by comparison.

Whether this medication is something to get excited about is completely subjective. We first need to await the results of the full clinical trials and make sure that it remains “safe” and maintains efficacy. When the drug does hit the market, it will take years before we are able to determine the long-term effects. Those who take the drug will essentially be “guinea pigs” for determining the long-term effects.

Since this drug was granted “Fast Track” status by the FDA, preliminary evidence is considered promising. The FDA doesn’t typically grant this status unless they see some impressive results in early phases with minimal side effects. It seems as though investigative treatments for depression are starting to become more common.

Due to the poor treatments currently available, drug and biotech companies are trying to develop something that will work for the masses. Drugs like GLYX-13 seem to be effective in a majority of individuals compared to current drugs. Another investigative antidepressant in the pipeline that offers fast-acting relief is ALKS 5461; people are excited about this drug due to the fact that many individuals have had success with Suboxone for depression.

Individuals who may have had success with ketamine for depression will likely be looking forward to the approval of GLYX-13 as it is considered similar. What do you think about GLYX-13 for the treatment of major depression? Feel free to share your thoughts, comments, and opinions in the comments section below.

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4 thoughts on “New Antidepressant GLYX-13 (Clinical Trials): Partial NMDA Receptor Agonist”

  1. Hello, thanks for your amazing depth of knowledge. Much appreciated. I do know that they are now using NMDA at the V.A. for treatment of vets (it may still be experimental). What I have read online, that when used within a therapeutic setting, only Very Small doses are given, and just a few doses seem to help a lot. It seems to open people up to some things that they have never experienced (good feelings) and that it also helps them to overcome prior traumas.

    I’m on an SSRI, and an SNRI, and anti-anxiety, mood stabilizer Very low doses of all, but it’s just not working as before. Was on Zoloft 19 years, and it was enough to allow me to function, but not Lose all my libido/emotions but it stopped working. Anyway, it’s just refreshing to read they are working on things such as this drug. Also, I have read they are working on brain imaging, where they will be able to tell exactly which areas of brain are not functioning well, etc. and be Way better able to target psych drugs.

    May be ready about 7-8 yrs from now? Maybe you have info on the site about that. So instead of being guinea pigs, they’ll be able to tell much more accurately what neuros to target etc. Thank you again for all you do and all your research. I hope I can get to a point where I can share more of my unique gifts… I have anhedonia, depression etc and keep way too isolated, as a way to control (feelings/emotions that are Too Much, overwhelming, etc). Thank you again and keep up the great work!

  2. Ketamine has changed my life in remarkable ways. I believe that GLYX-13 will be just as effective and perhaps cheaper (in that insurance may cover it). With so many deaths from suicide, especially from the military I think it is vital that a drug such as GLYX-13 be made available at the earliest possible time!

  3. I suffer from severe debilitating obsessive-compulsive disorder. My life is pretty much ruined due to the paralyzing symptoms. I would try GLYX-13, and wonder if it would help treat OCD, as OCD too is treated with antidepressants. Something more effective needs to be on the market.


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